1 La depresión como enfermedad sistémica: Duloxetina como paradigma terapéutico Jorge Luis Rovner 2006Key Point: I am presenting some information on a new drug from Lilly – it is under FDA review currently and has received an approvable letter.

2 Depresión—Una Causa principal de Discapacidad en todo el Mundo DALYs—2000 y 2020 Rango (Estimado)2 1 Infecciones respiratorias bajas Enfer. Isquémica cardíaca 2 Condiciones Perinatales Depresión Mayor Unipolar 3 HIV/SIDA Accidentes de tránsito 4 Depresión mayor unipolar Enfer. Cerebrovascular 5 Enfermedades Diarreicas Enfer. Pulmonar obstructiva crónica Depression—A Major Cause of Disability Worldwide DALYs—2000 and 2020 The burden of mental illness in general, and depression in particular, has long been underestimated. One in 6 persons in the United States will, at some point, suffer from major depression (Davidson and Meltzer-Brody, 1999). Depression is associated not only with significant morbidity, but with comorbid chronic illness and lost productivity because of excess mortality and morbidity. The massive Global Burden of Disease study (Murray and Lopez, 1996; World Health Report 2001), conducted by the World Health Organization, the World Bank, and Harvard University, developed a single measure to allow comparison of the burden of disease across many different diseases by including death and disability. This measure, disability-adjusted life-years (DALYs), calculates lost years of healthy life regardless of whether the years were lost to premature death or disability. Depression was estimated 4th in DALYs in 2000. It is estimated that by 2020, depression will rank second in DALYs. 1.World Health Report Mental Health: New Understanding, New Hope. Geneva, World Health Organization, Murray CJL, Lopez AD, eds. The Global Burden of Disease. Boston: Harvard University Press; 1996. DALYs=discapacidad-adjustada por años de vida.

3 HIPÓTESIS AMINÉRGICA DE LA DEPRESIÓN“ Los trastornos del ánimo son causados por una deficiencia en los niveles de serotonina o noradrenalina en los sitios receptores a dichas aminas que median sus acciones y efectos”

4 ISRS aumentan el nivel de 5-HT en la hendidura sináptica5-HT Transportador de recaptación (Bloqueado) NA Transp. de recaptación Representación Teórica NA 5-HT Key Points: SSRIs increase the amount of serotonin available in the synapse, but do not effect the levels of norepinephrine. 4

5 Inhibidores duales aumentan ambos niveles de neurotransmisores en la hendidura sinápticaNA Transportador de recaptura 5-HT Transportador de recaptura (Bloqueado) NA Transp. de recaptura (bloqueado) Representación teórica NA Key Points: By blocking both the serotonin and norepinephrine reuptake transporter, SNRIs increase the amount of both neurotransmitters available in the synapse.

6 HIPÓTESIS QUÍMICAS (MOLECULARES) DE LA DEPRESIÓNEstas hipótesis presumen que los estados depresivos del ánimo son producidos por cambios a largo término en la producción o actividad de moléculas en el cerebro y que los antidepresivos se contraponen a estos cambios moleculares (Nestler).

7 Dr. Luis M. Zieher

8 HIPÓTESIS DE REDES (NETWORK HYPOTHESIS)Esta nueva hipótesis propone que los problemas de comunicación intercelular dependientes de actividad deben subyacer a la depresión y que los antidepresivos actúan mejorando el procesamiento de la información en las redes neuronales afectadas

9

10

11 Estas redes se desarrollan a través de interacciones con el entorno y la estructura neuronal (y sus neurotransmisores) son constantemente redefinidos por procesos de plasticidad sináptica dependiente de actividad para procesar y almacenar de manera óptima la información relevante.

12 Los trastornos del SNC, incluyendo la depresión y la psicosis, deben representar disturbios en el procesamiento de las informaciones dependientes de actividad por parte del cerebro.

13 La Depresión … “ser incluída entre los trastornos de los circuitos frontoestriatales y de acciones dirigidas al objeto. Más aún, pacientes con enfermedades psiquiátricas como Esquizofrenia,desordenes obsesivos compulsivos,depresión y manía exhiben un espectro de desordenes de la acción dirigida al objeto, tales como apatía,agitación,comportamiento catatónico,conmpulsiones y comportamiento motor perseverativo.” F.Manes 2004

14 Los 5 circuitos frontoestriatales

15

16

17

18 Dr. Luis M. Zieher

19 Los patrones actuales de tratamiento: La Depresión está aún...Subdiagnósticada Menos del 50 % de los pacientes con Depresión Mayor son explicitamente reconocidos cuando están deprimidos1 Inadecuadamente tratada Solamente la mitad de los pacientes deprimidos reciben alguna forma de tratamiento para su enfermedad2 Solamente una cuarta parte de los pacientes recibe un tratamiento adecuado en dosis y duración 3 Today, depressive disorders are a threat worldwide to public health. These disorders are usually seen first by primary care physicians. Depressive disorders often go unrecognized, but even when recognized, they are frequently treated inadequately. Left untreated or undertreated, depressive disorders can lead to serious disability, suicide, and substantial increases in health care costs. 1. AHCPR Guidelines. Depression in Primary Care. Vol 1. US Department of Health and Human Services 2. Lepine C, et al. Int Clin Psychopharmacol. 1997;12:19-29. 3. Katon W, et al. Med Care. 1992;39(1):67-76.

20 Demografía por Género1 Femenino Masculino Categoría por Edad 0.01400.0120 Masculino 0.0100 0.0080 0.0060 0.0040 The difference in rate of depression among men and women begins in early adolescence and persists through the mid-50s. Women have a higher 12-month prevalence rate of depression largely due to higher risk of first onset. 0.0020 0.0000 0-4 5-9 10-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 Categoría por Edad 1. Kessler RC, et al. J Affective Disord. 1993;29:85-96.

21 Depresión: Síntomas Depresión Pensamientos Cambios SuicidasFalta de energía en el Sueño Dificultad Culpa y Depresión para Minusvalía Concentrarse Ánimo Deprimido Cambios en el Peso Fatiga Falta de interés APA, 1994, DSM-IV.

22 Síntomas Físicos Un Componente reconocido de la DepresiónCaracterísticas asociadas a episodios de depresión mayor “… preocupación excesiva acerca de salud física, y quejas de dolor (ej, dolores de cabeza o articulaciones, abdominales, u otros dolores).” De DSM-IV-TR, APA, 2000, p. 352. Physical Symptoms A Recognized Component of Depression

23 Sínptomas Físicos Comunes en Pacientes PsiquiátricosSíntoma Psiquiátrico Saludable Cansancio, falta de energía 85% 40% Jaquecas,dolores de cabeza 64% 48% Mareos o desmayos 60% 14% Debilidad en Partes del cuerpo 57% 23% Dolores Musculares, reumatismo 53% 27% Dolores estomacales 51% 20% Dolores de pecho 46% 14% Physical Symptoms Common in Psychiatric Patients Physical symptoms such as those listed here are common not just in primary care, but in psychiatric practice as well. Kellner and Sheffield administered a questionnaire to 100 psychiatric patients and 100 healthy persons. Both groups reported many physical symptoms, but psychiatric patients had a significantly higher prevalence of these symptoms. Adapted from Kellner R and Sheffield BF. Am J Psychiatry. 1973;130:

24 Tratamiento de mantenimiento: consensos de expertosWHO Consenso J. Affective Disorders, 1989 6 meses de terapia a partir de la resolución de los síntomas del episodio agudo Suecia Information från Läkemedelsverket Årgång 6, Nr 5, Dec 1995. Al menos 4-9 meses de terapia a partir de la resolución de los síntomas Reino Unido Brit. Med. Journal, 1992 4 a 6 meses de terapia a partir de la resolución de los síntomas Bélgica Al menos 4-9 meses de terapia a partir del comienzo de la mejoría sintomática. Commission De Transparence, Antidepresseurs, May 1994

25 Depresión: Metas del TratamientoSeveridad Tiempo Respuesta Recaída Recurrencia Mantenimiento Continuación Aguda Fases de Tratamiento Síntomas Remisión Síndrome No Depresión Recuperación X Con permiso de Kupfer, 1991 WPA/PTD Educational Program on Depressive Disorders WPA/PTD Educational Program on Depressive Disorders

26 Prevalencia de las tasas de Depresión en desordenes clínicos crónicosDepression is often present in patients with other illnesses. Compared to the general population, the prevalence of depression is higher in older patients, those with cancer, stroke, myocardial infarction (MI) during the days immediately following the event and 3 to 4 months later, and Parkinson's disease. Risk of depression increases in presence of chronic medical disorders:† Heart disease Cancer Stroke Functional impairments such as arthritis Alzheimer’s disease and other neurodegenerative diseases 1 of 4 patients in hospital medical units has clinically significant depressive symptoms.‡ † Wells KB, et al. Am J Psychiatry. 1988;145: ‡ Sullivan KW. J Clin Psychiatry. 1990;51(suppl):3-11. Adaptada de: WPA/PTD Educational Program on Depressive Disorders. Gavard JA, et al. Diabetes Care. 1993;16(8):

27 Por Qué Una Fase de Mantenimiento?AÑOS minutos a horas semanas horas a días

28 Serotonina y Noradrenalina en DepresiónCorteza Prefrontal Sistema Límbico Locus Coeruleus (fuente NA) Serotonin and Norepinephrine in Depression Most of the serotonin in the central nervous system is produced in the raphe nuclei. The largest cluster of noradrenergic cells in the central nervous system is located in the locus ceruleus. Both of these sources have ascending tracts which project to brain regions thought to be involved in depressive symptoms. Both also have descending tracts. Núcleo del Rafe (fuente 5-HT ) Kaplan and Sadock, eds. Comprehensive Textbook of Psychiatry 6th ed. Baltimore: Williams & Wilkins; 1995; p

29 5-HT y NA: El rol de ambos en cerebro y médula espinalCorteza Prefrontal Locus Ceruleus Núcleos Del Rafe Sístema Límbico Proyección Descendente NA Descendente Proyección Teórica Key Points: Serotonin has been implicated in depression through its brain pathways, starting in the Raphe nuclei and projecting up to the prefrontal cortex and limbic system. Norepinephrine has been similarly implicated, with its brain pathways starting in the Locus Ceruleus and projecting up to the same regions in the prefrontal cortex and limbic system. However, there are also downward projections of these serotonin and norepinephrine pathways from their brainstem nuclei into the spinal cord, and these pathways also have implications for the symptoms and treatment of depression. References: Stahl SM. The psychopharmacology of painful physical symptoms in depression. J Clin Psychiatry May;63(5):382-3. Stahl SM. J Clin Psychiatry ;63:

30 El rol de 5-HT y NA en percepción dolorosaSensorial Emocional Señal dolorosa NA 5-HT Vía descendente modulatoria del dolor Corteza Frontal Hipotalamo Lobulo Temporal Señal dolorosa ascendente Representación teórica Key Points: 5-HT and NE contribute to the centrally-mediated emotional and sensory response to pain. They also mediate pain perception through the descending modulatory pain pathway, which inhibits the ascending signal.

31 La historia del camino de neurotransmisión:No todo está en la cabezaDescending Pathway Vía Ascendente Descendente Representación teórica La disregulación de 5-HT y NA en el Cerebro está fuertemente asociada con Depresión. El cerebro puede percibir una señal dolorosa amplificada debido al desbalance 5-HT y NA en columna. Esto puede explicar porque los síntomas físicos son a menudo las principales quejas de pacientes deprimidos en la consulta general. You may wonder why depressed patients have these aches and pains? Key Points: Serotonin and Norepinephrine in the brain are implicated in depression Serotonin and Norepinephrine are present in the descending pain pathway in the spinal column and modulate pain through this pathway. Other Notes: Why the dual action (serotonin and norepinephrine) agents to treat aches and pains? 5-HT and NE are instrumental in the treatment of depression and pain. 5-HT and NE modify the effects of substance P, GLU, GABA and other pain mediators References: Stahl SM. The psychopharmacology of painful physical symptoms in depression. Journal of Clinical Psychiatry. 63(5):382-3, 2002 May. Blier P. Abbott FV. Putative mechanisms of action of antidepressant drugs in affective and anxiety disorders and pain. Journal of Psychiatry & Neuroscience. 26(1):37-43, 2001 Jan. Verma S, Gallagher RM. Evaluating and treating co-morbid pain and depression. International Review of Psychiatry. 2000;12(2): May. Adapted from: Stahl SM. J Clin Psychiatry. 2002;63(5): Blier P, Abbott FV. J Psychiatry Neurosci. 2001;26(1):37-43. Verma S, Gallagher RM. Int Rev Psychiatry. 2000;12:

32 Depresión: Actividad alterada en las vías descendentes 5-HT y NASeñal dolor NA 5-HT Key Points: 5-HT and NE are the neurotransmitters in the descending inhibitory pain pathway. If depression has caused a decrease in these neurotransmitters, then there would be a decrease in the pain inhibition mediated by this spinal pathway, leading to increased pain perception. 32 Representación teórica

33 Tanto 5-HT como NA median un amplio espectro de síntomas depresivos5-HT y NA: Sus roles en los síntomas emocionales y físicos Tanto 5-HT como NA median un amplio espectro de síntomas depresivos Basados en perfiles superpuestos y distinguibles Key Points: Antidepressants that effect either serotonin or norepinephrine specifically are effective agents. But while serotonin and norepinephrine do mediate a broad range of depressive symptoms, they do have distinguishable profiles in mediating symptoms. Therefore, dual-acting agents may provide benefits in treating the full range of depressive symptoms, both emotional and physical. Los agentes de doble acción pueden proveer efectos sobre múltiples síntomas emocionales y físicos asociados a la Depresión

34 Serotonina y Noradrenalina: Efecto en Síntomas DepresivosVigilancia Ansiedad Irritabilidad Impulsividad Motivación Sexo Apetito Agresión Función Cognitiva Humor Emoción Serotonina dolor Serotonin and Norepinephrine: Effect on Depressive Symptoms One would expect from the research cited heroin that currently available classes of antidepressants would have overlapping spectrums of therapeutic effects and that, while all might be effective in many patients, some will be more useful according to individual needs. It appears that agents that act on both 5-HT and NE systems act on a wider spectrum of symptoms of depression, including painful symptoms. Balanced reuptake inhibition may be optimal to make the agent effective across the range of dosing. Los agentes de acción dual pueden brindar el más amplio espectro de efectos terapeúticos en un rango pleno de síntomas emocionales y físicos de depresión Delgado, unpublished.

35 Redefiniendo Eficacia Remisión, No solo Respuesta1Respuesta al Tratamiento 50% de redución de síntomas basado en Escala HAMD-17 puntos Remisión Reducción en la Escala HAMD-17 puntos a ≤7 puntos sin tomar en cuenta el puntaje basal2 menor riesgo de recaída3 Mejora de funcionamiento físico y social4 Redefining Efficacy Remission, Not Just Response Success in treatment of depression has been redefined in recent years. Previously, treatment response, generally a 50% reduction in symptoms, was considered adequate. Success is now defined by remission. Different definitions of remission are used, but one of the most common in clinical trials is a reduction in HAMD-17 to 7 or less. HAMD-17 refers to the total score on the 17-item semi-structured Hamilton Rating Scale for Depression. Treatment to an endpoint of symptom remission leads to a lower risk of relapse and improved occupational and social functioning 1. Ballenger. J Clin Psychiatry. 1999;60(suppl 22):29-34; Nierenberg et al. J Clin Psychiatry. 1999;60(suppl 22):7-11. 2. Fawcett et al. J. Clin Psychiatry. 1997;58 (suppl 6):32-38. 3. Paykel et al. Psychol Med. 1995;25: 4. Doraiswamy et al. Am J Geriatr Psychiatry. 2001;9:4:

36 Remisión : menor riesgo de Recaída76% Tasa de recaída (%) 25% Remission Lower Risk of a Relapse Patients who achieve symptom remission are far less likely to have a relapse. Furthermore, those achieve symptom remission and do relapse, do so later in the course than those with residual symptoms (Judd et al. 1998, Van London et al. 1998). Síntomas Residuales Remisión Paykel et al. Psychol Med. 1995;25:

37 Remisión: Mejora del Funcionamiento físico y social† * SF-36 puntaje promedio Remission: Improved Physical and Social Functioning Remitters scored better than partial responders on a number of quality of life measures; including physical and social functioning. *p< †p<0.09. Doraiswamy et al. Am J Geriatr Psychiatry. 2001;9:4:

38 La remisión sintomática en Depresión también depende de la reducción de los síntomas físicos dolorosos

39 Duloxetina 60 mg una vez al día vs. Placebo en DDM :Dolor GlobalSemanas 1 1 2 2 3 3 4 4 5 5 6 6 7 7 8 8 9 9 p=.055 2 2 Duloxetina Duloxetine - - 2 2 60 mg QD 60 mg QD Media de Cambio desde Basal (mm) Escala Visual Análoga para dolor global (n=120) (n=120) - - 4 4 Placebo Placebo (n=113) (n=113) Mejoría - - 6 6 Key Points: Duloxetine produced significantly greater improvement on the Visual Analog Scale for overall pain than placebo, starting at 2 weeks and was sustained at weeks 3, 5, and 7 by mixed model repeated measures (MMRM) analysis. At endpoint, the separation was marginally significant (p=.055). Pain severity was assessed using self-report visual-analog scales (VAS). Patients would make a tick mark along a 100-mm long line according to the level of their pain during the previous week, from 0 (no pain) to 100 (as severe as I can imagine). Background: The data presented here are from one of two identical but independent, 9-week, randomized, double-blind, placebo-controlled studies in adult outpatients who met DSM-IV criteria for major depressive disorder (MDD). None of the patients were considered treatment-refractory. Entry criteria included a DSM-IV diagnosis of major depression with a severity specified by a 17-item Hamilton Depression Rating Scale (HAMD-17) total score > 15 and a Clinical Global Impression of Severity (CGI-S) score of > 4 (indicating at least moderately ill) at baseline for out-patients at least 18 years of age.The relatively low cut-off of 15 on the 17-item HAMD was chosen to minimize encouraging raters to artificially inflate baseline scores, to provide greater accuracy. Note that all patients still had to meet full DSM-IV criteria for MDD and have a CGI-S > 4. Pain severity was assessed using self-report visual-analog scales (VAS). Patients would make a tick mark along a 100-mm long line according to the level of their pain during the previous week, from 0 (no pain) to 100 (as severe as I can imagine). References: Detke MJ, Lu Y, Goldstein DJ, Hayes JR, Demitrack MA. Duloxetine, 60 mg once daily, for major depressive disorder: a randomized double-blind placebo-controlled trial. J Clin Psychiatry. 2002;63(4): Data: Weeks DLX 60 mg QD (n=120) Placebo (n=113) Study: F1J-MC-HMBH (A) - - 8 8 * * *p<.05 *p<.05 * * p=.055 - - 10 10 MMRM MMRM * * * * - - 12 12 Detke MJ, et al. J Clin Psychiatry. 2002;63:

40 Duloxetina 60 mg una vez al día vs. Placebo en DDM: Dolor de espaldasSemanas *p<.05 **p<.001 MMRM * ** 1 1 2 2 3 3 4 4 5 5 6 6 7 7 8 8 9 9 - - 2 2 Duloxetine Duloxetina - - 4 4 60 mg QD 60 mg QD Media de Cambio desde basal (mm) (n=120) (n=120) - - 6 6 Placebo Placebo Mejoría VAS para Dolor de Espaldas (n=114) (n=114) - - 8 8 Key Points: Duloxetine produced significantly greater improvement on the Visual Analog Scale for back pain than placebo, starting at 1 week and continuing at each point throughout the study by mixed model repeated measures( MMRM) analysis. Background: The data presented here are from one of two identical but independent, 9-week, randomized, double-blind, placebo-controlled studies in adult outpatients who met DSM-IV criteria for major depressive disorder (MDD). None of the patients were considered treatment-refractory. Entry criteria included a DSM-IV diagnosis of major depression with a severity specified by a 17-item Hamilton Depression Rating Scale (HAMD-17) total score > 15 and a Clinical Global Impression of Severity (CGI-S) score of > 4 (indicating at least moderately ill) at baseline for out-patients at least 18 years of age.The relatively low cut-off of 15 on the 17-item HAMD was chosen to minimize encouraging raters to artificially inflate baseline scores, to provide greater accuracy. Note that all patients still had to meet full DSM-IV criteria for MDD and have a CGI-S > 4. Pain severity was assessed using self-report visual-analog scales (VAS). Patients would make a tick mark along a 100-mm long line according to the level of their pain during the previous week, from 0 (no pain) to 100 (as severe as I can imagine). References: Detke MJ, Lu Y, Goldstein DJ, Hayes JR, Demitrack MA. Duloxetine, 60 mg once daily, for major depressive disorder: a randomized double-blind placebo-controlled trial. J Clin Psychiatry. 2002;63(4): Data: Weeks DLX 60 mg QD (n=120) Placebo (n=114) Study: F1J-MC-HMBH (A) * - - 10 10 ** *p<.05 - - 12 12 ** * **p<.001 ** ** - - 14 14 MMRM Detke MJ, et al. J Clin Psychiatry. 2002;63:

41 Duloxetina 60 mg vs. Placebo en DDM: Visual Analog Scale (VAS):Principal efecto del tratamientoVAS para severidad del dolor e interferencia a 9 semanas -50 -40 -30 -20 -10 Dolor Global Espaldas Hombros Cefalea al despertar Interferencia con la vida diaria Camio en VAS (%) Duloxetina 60 mg QD (n=120) Placebo (n=113) Mejoría ** * *p<.05 **p<.001 Main Effect Key Points: Duloxetine produced significantly greater improvement on the Visual Analog Scale (VAS) for back pain, overall pain, shoulder pain, pain interference with daily activities, and pain while awake than placebo at endpoint (week-9) by main effects analysis. The treatment effect of duloxetine on headache was numerically superior to placebo. The main effect of treatment analysis estimates the treatment effects pooled across all patient visits and is similar to an area under the curve analysis. Background: The data presented here are from one of two identical but independent, 9-week, randomized, double-blind, placebo-controlled studies in adult outpatients who met DSM-IV criteria for major depressive disorder (MDD). None of the patients were considered treatment-refractory. Entry criteria included a DSM-IV diagnosis of major depression with a severity specified by a 17-item Hamilton Depression Rating Scale (HAMD-17) total score > 15 and a Clinical Global Impression of Severity (CGI-S) score of > 4 (indicating at least moderately ill) at baseline for out-patients at least 18 years of age.The relatively low cut-off of 15 on the 17-item HAMD was chosen to minimize encouraging raters to artificially inflate baseline scores, to provide greater accuracy. Note that all patients still had to meet full DSM-IV criteria for MDD and have a CGI-S > 4. Pain severity was assessed using self-report visual-analog scales (VAS). Patients would make a tick mark along a 100-mm long line according to the level of their pain during the previous week, from 0 (no pain) to 100 (as severe as I can imagine). References: Nemeroff CB, Schatzberg AF, Goldstien DJ, Detke MJ, Mallinckrodt CH, Lu Y, Tran PV. Duloxetine for the Treatment of Major Depressive Disorder. Psychopharmacology Bulletin. 2002;36(4): Data: Overall Back Shoulder Headache Pain Int w/ Pain Pain Pain While Awake Daily Activity DLX 60 mg QD (n=120) Placebo (n=113) Study: F1J-MC-HMBH (A) Nemeroff CB, et al. Psychopharm Bull. 2002;36:

42 Duloxetina 60 mg Una vez al día vs. Placebo en Depresión MayorDuloxetina 60 mg Una vez al día vs. Placebo en Depresión Mayor.Datos conjuntos: Visual Analog Scale (VAS) Principal Efecto de tratamiento ** * Dolor Global Interferencia Vida diaria Dolor de Espaldas Dolor de Hombros Dolor al despertar Cefalea - - 10 10 Duloxetine Duloxetina - - 20 20 60 mg QD 60 mg QD * (n=240) (n=240) Cambio en VAS (%) Mejoría - - 30 30 Placebo Placebo ** * (n=246) (n=246) Key Points: Duloxetine produced significantly greater improvement on the Visual Analog Scale (VAS) for back pain, overall pain, shoulder pain, pain interference with daily activities, and pain while awake than placebo at endpoint (week-9) by main effects analysis. The treatment effect of duloxetine on headache was numerically superior to placebo. The main effect of treatment analysis estimates the treatment effects pooled across all patient visits and is similar to an area under the curve analysis. Background: The data presented here are from two identical but independent, 9-week, randomized, double-blind, placebo-controlled studies in adult outpatients who met DSM-IV criteria for major depressive disorder (MDD). None of the patients were considered treatment-refractory. Entry criteria included a DSM-IV diagnosis of major depression with a severity specified by a 17-item Hamilton Depression Rating Scale (HAMD-17) total score > 15 and a Clinical Global Impression of Severity (CGI-S) score of > 4 (indicating at least moderately ill) at baseline for out-patients at least 18 years of age.The relatively low cut-off of 15 on the 17-item HAMD was chosen to minimize encouraging raters to artificially inflate baseline scores, to provide greater accuracy. Note that all patients still had to meet full DSM-IV criteria for MDD and have a CGI-S > 4. Pain severity was assessed using self-report visual-analog scales (VAS). Patients would make a tick mark along a 100-mm long line according to the level of their pain during the previous week, from 0 (no pain) to 100 (as severe as I can imagine). References: Fava M, Wohlreich MM, Mallinckrodt CH, Lu Y, Detke MJ. “Efficacy of Duloxetine (60 mg QD) in the Treatment of Painful Physical Symptoms in Patients with Major Depression”. Presented at the 156th Annual Meeting of the APA; San Francisco, CA; May 17-22, 2003. Data: Overall Back Shoulder Headache Pain Int w/ Pain Pain Pain While Awake Daily Activity DLX 60 mg QD (n=240) Placebo (n=246) Study: F1J-MC-HMBH (AB) * *p<.05 *p<.05 - - 40 40 ** **p<.001 **p<.001 Principal efecto Main Effect - - 50 50 VAS Severidad e interferencia a 9 semanas Fava M, et al. Presented at the 156th Annual Meeting of the APA; San Francisco, CA; May 17-22, 2003.

43 Síntomas Físicos Dolorosos en Depresión Deberían Alertar al Clínico para Considerar el DiagnósticoValor Positivo predictivo para depresión (%) Painful Physical Symptoms in Depression: Should Alert the Clinician to Consider the Diagnosis Gerber and colleagues studied the physical complaints of 1042 patients who presented for primary care in 4 internist offices. Each patient completed a 49-item, self-report screening inventory asking about the presence of a variety of symptoms in the preceding week. Embedded in this inventory were items comprising the Hopkins Symptoms Checklist depression scale. Physical symptoms that discriminated between depressed and non-depressed patients included nonspecific musculoskeletal complaints (positive predictive value [PPV] 43%) and back pain (PPV 39%). The investigators concluded that clinicians should have a high index of suspicion for depression when such symptoms are present. Quejas musculoesqueléticas inespecíficas Dolor de espalda Gerber PD et al. J Gen Intern Med. 1992;7:

44 Cymbalta: Eficacia en el tratamiento de la DepresiónKey Point: I am presenting some information on a new drug from Lilly – it is under FDA review currently and has received an approvable letter.

45 Cymbalta: Estudios de corto plazo vs placeboKey Point: I am presenting some information on a new drug from Lilly – it is under FDA review currently and has received an approvable letter.

46 Cymbalta 60 mg vs. Placebo en Depresión MayorProbabilidad estimada de Respuesta En semana 9 80 80 70 70 Duloxetina Duloxetine * 60 mg QD 60 mg QD 60 60 (n=121) (n=121) 62% 62% 50 50 Porcentaje de pacientes 40 40 Placebo Placebo (n=115) (n=115) 30 30 29% 29% Key Points: Patients treated with duloxetine had a significant response rate vs. placebo at endpoint, 62% vs 29% by mixed model repeated measures (MMRM) analysis. (45% vs. 23% by last observation carried forward (LOCF) analysis). Background: The data presented here are from one of two identical but independent, 9-week, randomized, double-blind, placebo-controlled studies in adult outpatients who met DSM-IV criteria for major depressive disorder (MDD). None of the patients were considered treatment-refractory. Entry criteria included a DSM-IV diagnosis of major depression with a severity specified by a 17-item Hamilton Depression Rating Scale (HAMD-17) total score > 15 and a Clinical Global Impression of Severity (CGI-S) score of > 4 (indicating at least moderately ill) at baseline for out-patients at least 18 years of age.The relatively low cut-off of 15 on the 17-item HAMD was chosen to minimize encouraging raters to artificially inflate baseline scores, to provide greater accuracy. Note that all patients still had to meet full DSM-IV criteria for MDD and have a CGI-S > 4. References: Detke MJ, Lu Y, Goldstein DJ, Hayes JR, Demitrack MA. Duloxetine, 60 mg once daily, for major depressive disorder: a randomized double-blind placebo-controlled trial. J Clin Psychiatry. 2002;63(4): Data: % DLX 60 mg QD (n=121) 62 Placebo (n=115) 29 Study: F1J-MC-HMBH(A) *p<.001 20 20 MMRM 10 10 Respuesta se define como > 50% disminuido desde basal en HAMD Total . 17 Detke MJ, et al. J Clin Psychiatry. 2002;63:

47 Duloxetina 60 mg vs. Placebo en Depresión MayorProbabilidad estimada de remisión En semana 9 60 60 Duloxetina Duloxetine 60 mg QD 60 mg QD 50 50 * (n=121) (n=121) 40 40 44% 44% Placebo Placebo Porcentaje de pacientes 30 30 (n=115) (n=115) 20 20 Key Points: Patients treated with duloxetine had a significant remission rate vs. placebo at 9-weeks of treatment (44% vs. 16%), by mixed model repeated measures (MMRM) analysis. Background: The data presented here are from one of two identical but independent, 9-week, randomized, double-blind, placebo-controlled studies in adult outpatients who met DSM-IV criteria for major depressive disorder (MDD). None of the patients were considered treatment-refractory. Entry criteria included a DSM-IV diagnosis of major depression with a severity specified by a 17-item Hamilton Depression Rating Scale (HAMD-17) total score > 15 and a Clinical Global Impression of Severity (CGI-S) score of > 4 (indicating at least moderately ill) at baseline for out-patients at least 18 years of age.The relatively low cut-off of 15 on the 17-item HAMD was chosen to minimize encouraging raters to artificially inflate baseline scores, to provide greater accuracy. Note that all patients still had to meet full DSM-IV criteria for MDD and have a CGI-S > 4. References: Detke MJ, Lu Y, Goldstein DJ, Hayes JR, Demitrack MA. Duloxetine, 60 mg once daily, for major depressive disorder: a randomized double-blind placebo-controlled trial. J Clin Psychiatry. 2002;63(4): Data: % DLX 60 mg QD (n=121) 44 Placebo (n=115) 16 Study: F1J-MC-HMBH(A) *p<.001 10 10 16% 16% MMRM Remisión definida como HAMD total de 17 Detke MJ, et al. J Clin Psychiatry. 2002;63:

48 Cymbalta 60 mg vs. Placebo en Depresión Mayor: HAMD17 Total- 12 10 8 6 4 2 1 3 5 7 9 Semanas Media de Cambio desde Basal (HAMD 17 Punt.Total) Duloxetina 60 mg QD (n=121) Placebo (n=115) * *p<.001 MMRM 1 1 2 2 3 3 4 4 5 5 6 6 7 7 8 8 9 9 - - 2 2 - - 4 4 60 mg QD 60 mg QD (n=121) (n=121) Mejoría - - 6 6 * ) ) Placebo Placebo 17 17 (n=115) (n=115) Key Point: Duloxetine produced significantly greater improvement on the HAMD17 total score than placebo, starting at 2 weeks and continuing at each point throughout the study by MMRM (mixed model repeated measures) analysis. Background: The data presented here are from one of two identical but independent, 9-week, randomized, double-blind, placebo-controlled studies in adult outpatients who met DSM-IV criteria for major depressive disorder (MDD). None of the patients were considered treatment-refractory. Entry criteria included a DSM-IV diagnosis of major depression with a severity specified by a 17-item Hamilton Depression Rating Scale (HAMD-17) total score > 15 and a Clinical Global Impression of Severity (CGI-S) score of > 4 (indicating at least moderately ill) at baseline for out-patients at least 18 years of age.The relatively low cut-off of 15 on the 17-item HAMD was chosen to minimize encouraging raters to artificially inflate baseline scores, to provide greater accuracy. Note that all patients still had to meet full DSM-IV criteria for MDD and have a CGI-S > 4. References: Detke MJ, Lu Y, Goldstein DJ, Hayes JR, Demitrack MA. Duloxetine, 60 mg once daily, for major depressive disorder: a randomized double-blind placebo-controlled trial. J Clin Psychiatry. 2002;63(4): Data: Weeks DLX 60 mg QD (n=121) Placebo (n=115) Study: F1J-MC-HMBH (A) - - 8 8 * (HAMD (HAMD * - - 10 10 *p<.001 * * MMRM - - 12 12 Detke MJ, et al. J Clin Psychiatry. 2002;63:

49 Duloxetina 60 mg vs. Placebo en Depresión Mayor PGI-Mejoría2.0 2.5 3.0 3.5 4.0 1 2 3 4 5 6 7 8 9 Semanas Media Cambio PGI - Duloxetine 60 mg QD (n=119) Placebo (n=114) *p=.003 **p<.001 MMRM 1 1 2 2 3 3 4 4 5 5 6 6 7 7 8 8 9 9 4.0 4.0 3.5 3.5 Duloxetina 60 mg QD 60 mg QD (n=119) (n=119) Mejoría 3.0 3.0 ** ** Placebo Placebo * * (n=114) (n=114) Key Points: Duloxetine produced significantly greater improvement on the patient-rated PGI-Improvement than placebo, starting at 2 weeks and continuing at each point throughout the study using MMRM (mixed model repeated measures). The Patient Global Impression of Improvement scale is a self-assessment of improvement since starting study drug. A score of 4 indicates “no change,” a score of 3 indicates “a little better,” a score of 2 indicates “much better,” and a score of 1 indicates “very much better.” Background: The data presented here are from one of two identical but independent, 9-week, randomized, double-blind, placebo-controlled studies in adult outpatients who met DSM-IV criteria for major depressive disorder (MDD). None of the patients were considered treatment-refractory. Entry criteria included a DSM-IV diagnosis of major depression with a severity specified by a 17-item Hamilton Depression Rating Scale (HAMD-17) total score > 15 and a Clinical Global Impression of Severity (CGI-S) score of > 4 (indicating at least moderately ill) at baseline for out-patients at least 18 years of age.The relatively low cut-off of 15 on the 17-item HAMD was chosen to minimize encouraging raters to artificially inflate baseline scores, to provide greater accuracy. Note that all patients still had to meet full DSM-IV criteria for MDD and have a CGI-S > 4. References: Data on file, Lilly Research Laboratories. Data: Weeks DLX 60 mg QD (n=119) Placebo (n=114) Study: F1J-MC-HMBH (A) - - ** ** 2.5 2.5 ** ** ** ** *p=.003 **p<.001 2.0 2.0 MMRM Data on file, Lilly Research Laboratories.

50 Cymbalta 60 mg vs. Placebo en Depresión Mayor: HAMD17 Item 1- 2.0 1.5 1.0 0.5 0.0 1 2 3 4 5 6 7 8 9 Semanas Media de Cambio desde Basal (HAMD 17 Item 1 Humor Depresivo) Duloxetina 60 mg QD (n=121) Placebo (n=115) ** * *p=.014 **p<.001 MMRM 1 1 2 2 3 3 4 4 5 5 6 6 7 7 8 8 9 9 0.0 0.0 - - 0.5 0.5 * 60 mg QD 60 mg QD (n=121) (n=121) Mejoría - - - - 1.0 1.0 Placebo Placebo ** Item 1 Item 1 (n=115) (n=115) Key Point: Duloxetine produced significantly greater improvement on item-1 (depressed mood) of the HAMD17 than placebo, starting at 1 week and continuing at each point throughout the study by MMRM (mixed model repeated measures) analysis. Background: The data presented here are from one of two identical but independent, 9-week, randomized, double-blind, placebo-controlled studies in adult outpatients who met DSM-IV criteria for major depressive disorder (MDD). None of the patients were considered treatment-refractory. Entry criteria included a DSM-IV diagnosis of major depression with a severity specified by a 17-item Hamilton Depression Rating Scale (HAMD-17) total score > 15 and a Clinical Global Impression of Severity (CGI-S) score of > 4 (indicating at least moderately ill) at baseline for out-patients at least 18 years of age.The relatively low cut-off of 15 on the 17-item HAMD was chosen to minimize encouraging raters to artificially inflate baseline scores, to provide greater accuracy. Note that all patients still had to meet full DSM-IV criteria for MDD and have a CGI-S > 4. References: Data on file, Lilly Research Laboratories. Data: Weeks DLX 60 mg QD (n=121) Placebo (n=115) Study: F1J-MC-HMBH (A) - - 1.5 1.5 ** 17 17 ** ** *p=.014 ** (HAMD (HAMD **p<.001 - - 2.0 2.0 MMRM Data on file, Lilly Research Laboratories.

51 Duloxetina 60 mg vs. Placebo en TDM: HAMD17 Subescala AnsiedadKey Points: Duloxetine produced significantly greater improvement on the HAMD17 anxiety subscale than placebo, starting at 2 weeks and continuing at each point throughout the study by mixed model repeated measures (MMRM) analysis. The anxiety subscale of the HAMD17 includes the following items: item-10, psychic anxiety; item-11, somatic anxiety; item-12, somatic symptoms (GI); item-13, somatic symptoms (general); item-15, hypochondriasis; and item-17, insight. Background: The data presented here are from one of two identical but independent, 9-week, randomized, double-blind, placebo-controlled studies in adult outpatients who met DSM-IV criteria for major depressive disorder (MDD). None of the patients were considered treatment-refractory. Entry criteria included a DSM-IV diagnosis of major depression with a severity specified by a 17-item Hamilton Depression Rating Scale (HAMD-17) total score > 15 and a Clinical Global Impression of Severity (CGI-S) score of > 4 (indicating at least moderately ill) at baseline for out-patients at least 18 years of age.The relatively low cut-off of 15 on the 17-item HAMD was chosen to minimize encouraging raters to artificially inflate baseline scores, to provide greater accuracy. Note that all patients still had to meet full DSM-IV criteria for MDD and have a CGI-S > 4. References: Dunner DL, Goldstein DJ, Mallinckrodt C, Lu Y, Detke MJ. Duloxetine in Treatment of Anxiety Symptoms Associated with Depression. Depression and Anxiety. 2003;18:53-61. Data: Weeks DLX 60 mg QD (n=121) Placebo (n=115) Study: F1J-MC-HMBH (A) Dunner DL, et al. Depress Anxiety. 2003;18:53-61.

52 Duloxetine 60 mg vs. Placebo en TDM: HAMD17 Item 10 Ansiedad PsiquícaKey Points: Duloxetine produced significantly greater improvement on item-10 (psychic anxiety) of the HAMD17 than placebo, starting at 1 week and continuing at each point throughout the study by mixed model repeated measures (MMRM) analysis. Background: The data presented here are from one of two identical but independent, 9-week, randomized, double-blind, placebo-controlled studies in adult outpatients who met DSM-IV criteria for major depressive disorder (MDD). None of the patients were considered treatment-refractory. Entry criteria included a DSM-IV diagnosis of major depression with a severity specified by a 17-item Hamilton Depression Rating Scale (HAMD-17) total score > 15 and a Clinical Global Impression of Severity (CGI-S) score of > 4 (indicating at least moderately ill) at baseline for out-patients at least 18 years of age.The relatively low cut-off of 15 on the 17-item HAMD was chosen to minimize encouraging raters to artificially inflate baseline scores, to provide greater accuracy. Note that all patients still had to meet full DSM-IV criteria for MDD and have a CGI-S > 4. References: Data on file, Lilly Research Laboratories. Data: Weeks DLX 60 mg QD (n=121) Placebo (n=115) Study: F1J-MC-HMBH (A) Data on file, Lilly Research Laboratories.

53 Cymbalta: Estudios de corto plazo vs FluoxetinaKey Point: I am presenting some information on a new drug from Lilly – it is under FDA review currently and has received an approvable letter.

54 Duloxetina: Subescala HAMD17 Ansiedad/SomatizaciónKey Points: Duloxetine produced significantly greater improvement on the HAMD17 anxiety subscale than placebo endpoint (8-weeks), by mixed model repeated measures (MMRM) analysis. Duloxetine produced significantly greater improvement on the HAMD17 anxiety subscale than fluoxetine at endpoint (8-weeks), but fluoxetine was underpowered in this study. The anxiety subscale of the HAMD17 includes the following items: item-10, psychic anxiety; item-11, somatic anxiety; item-12, somatic symptoms (GI); item-13, somatic symptoms (general); item-15, hypochondriasis; and item-17, insight. Background: The data presented here are from one of two identical but independent 8-week, randomized, double-blind, placebo-controlled, phase II studies in adult outpatients (18-65 years of age) who met DSM-IV criteria for major depressive disorder (MDD). The duloxetine dose was titrated in the first 3-weeks from 40 mg/day to 120 mg/day (60 mg BID). None of the patients were considered treatment-refractory. Entry criteria included a DSM-IV diagnosis of major depression with a severity specified by a 17-item Hamilton Depression Rating Scale (HAMD-17) total score > 15 and a Clinical Global Impression of Severity (CGI-S) score of > 4 (indicating at least moderately ill) at baseline.The relatively low cut-off of 15 on the 17-item HAMD was chosen to minimize encouraging raters to artificially inflate baseline scores, to provide greater accuracy. Note that all patients still had to meet full DSM-IV criteria for MDD and have a CGI-S > 4. References: Dunner DL, Goldstein DJ, Mallinckrodt C, Lu Y, Detke MJ. Duloxetine in Treatment of Anxiety Symptoms Associated with Depression. Depression and Anxiety. 2003;18:53-61. Data: Weeks Placebo (n = 66) FLX 20 mg QD (n = 33) DLX 120 mg per day (n = 68) Study: F1J-MC-HMAQ (A) Dunner DL, et al. Depress Anxiety. 2003;18:53-61.

55 Duloxetina : HAMD17 Tasas de RemisiónProbabilidad estimada de remisión en semana 8 70 70 Duloxetine Duloxetina 60 60 120 mg/día 120 mg/day * * (n=66) (n=66) 56% 56% 50 50 Fluoxetine Fluoxetina 20 mg QD 20 mg QD 40 40 (n=33) (n=33) Porcentaje de pacientes Placebo Placebo 30 30 32% 32% 30% 30% (n=68) (n=68) Key Point: Remission rates were statistically significantly greater for duloxetine than for fluoxetine or placebo by mixed models repeated measures (MMRM) analysis. Background: The data presented here are from one of two identical but independent 8-week, randomized, double-blind, placebo-controlled, phase II studies in adult outpatients (18-65 years of age) who met DSM-IV criteria for major depressive disorder (MDD). The duloxetine dose was titrated in the first 3-weeks from 40 mg/day to 120 mg/day (60 mg BID). None of the patients were considered treatment-refractory. Entry criteria included a DSM-IV diagnosis of major depression with a severity specified by a 17-item Hamilton Depression Rating Scale (HAMD-17) total score > 15 and a Clinical Global Impression of Severity (CGI-S) score of > 4 (indicating at least moderately ill) at baseline.The relatively low cut-off of 15 on the 17-item HAMD was chosen to minimize encouraging raters to artificially inflate baseline scores, to provide greater accuracy. Note that all patients still had to meet full DSM-IV criteria for MDD and have a CGI-S > 4. References: Goldstein DJ, Mallinckrodt C, Lu Y, Demitrack MA. Duloxetine in the Treatment of Major Depressive Disorder: A Double-Blind Clinical Trial. J Clin Psychiatry. 2002;63(3): Data: % Duloxetine 120 mg per day (n = 66) 56 Fluoxetine 20 mg QD (n = 33) 30 Placebo (n-68) 32 Study: F1J-MC-HMAQ (A) 20 20 10 10 *p=.022 *p=.022 vs. placebo vs. placebo MMRM MMRM Remisión definida con HAMD total de < 7 17 Goldstein DJ, et al. J Clin Psychiatry. 2002;63:

56 Cymbalta: Estudios de corto plazo vs ParoxetinaKey Point: I am presenting some information on a new drug from Lilly – it is under FDA review currently and has received an approvable letter.

57 Tasas de Remisión: Estudio de Hallazgo de dosisKey Points: Remission rates were significantly greater (p<0.01) for duloxetine 80 mg/day than placebo. Duloxetine 40 mg/day was numerically superior to placebo by last observation carried forward (LOCF) analysis. Background: This study data presented here are from one of two identical studies that examined the efficacy of lower (40 mg/day) and higher (80 mg/day) duloxetine doses given in a twice-daily dosing regimen as 20 mg BID or 40 mg BID. It also incorporated a paroxetine (20 mg/day) arm to compare duloxetine’s efficacy and tolerability with that of an SSRI, which acts only on the serotonin neurotransmitter. This was an 8-week, randomized, double-blind, controlled trial in outpatients who met DSM-IV criteria for major depression. None of the patients were considered treatment-refractory. Entry criteria included a DSM-IV diagnosis of major depression with a severity specified by a 17-item Hamilton Depression Rating Scale (HAMD-17) total score > 15 and a Clinical Global Impression of Severity (CGI-S) score of > 4 (indicating at least moderately ill) at baseline for out-patients at least 18 years of age. References: Goldstein D, Lu Y, Detke M, Wiltse C, Mallinckrodt CH, Demitrack MA. “Duloxetine vs. Paroxetine in the Treatment of Depression” Presented at the 155th Annual Meeting of the American Psychiatric Association (APA); Philadelphia, PA; May 18-23, 2002. Data: % Duloxetine 80 mg per day (n = 86) 50 Duloxetine 40 mg per day (n = 84) 35 Paroxetine 20 mg QD (n = 84) 37 Placebo (n = 88) 30 Study: F1J-MC-HMAT (Study B) Goldstein DJ, et al. Presented at the 155th Annual Meeting of the APA; Philadelphia, PA; May 18-23, 2002.

58 Duloxetina :Tasas de remisión comparadasKey Point: Remission rates were significantly greater (p<0.01) for duloxetine 80 mg/day than placebo. Duloxetine 40 mg/day was numerically superior to both paroxetine 20 mg/day and placebo by mixed models repeated measures (MMRM) analysis. Background: This study data presented here are from one of two identical studies that examined the efficacy of lower (40 mg/day) and higher (80 mg/day) duloxetine doses given in a twice-daily dosing regimen as 20 mg BID or 40 mg BID. It also incorporated a paroxetine (20 mg/day) arm to compare duloxetine’s efficacy and tolerability with that of an SSRI, which acts only on the serotonin neurotransmitter. This was an 8-week, randomized, double-blind, controlled trial in outpatients who met DSM-IV criteria for major depression. None of the patients were considered treatment-refractory. Entry criteria included a DSM-IV diagnosis of major depression with a severity specified by a 17-item Hamilton Depression Rating Scale (HAMD-17) total score > 15 and a Clinical Global Impression of Severity (CGI-S) score of > 4 (indicating at least moderately ill) at baseline for out-patients at least 18 years of age. References: Goldstein D, Lu Y, Detke M, Wiltse C, Mallinckrodt CH, Demitrack MA “Duloxetine vs. Paroxetine in the Treatment of Depression”. Presented at the 155th Annual Meeting of the American Psychiatric Association (APA); Philadelphia, PA; May 18-23, 2002. Data: % Duloxetine 80 mg per day (n = 86) 57 Duloxetine 40 mg per day (n = 84) 36 Paroxetine 20 mg QD (n = 84) 34 Placebo (n = 88) 25 Study: F1J-MC-HMAT (Study B) Goldstein DJ, et al. Presented at the 155th Annual Meeting of the APA; Philadelphia, PA; May 18-23, 2002.

59 Semanas postrandomnizaciónCymbalta en el Tratamiento de Síntomas de ansiedad asociado a Depresión Sub-escala HAMD-17 Ansiedad/Somatización Semanas postrandomnización LS cambio promedio Desde nivel basal ** Effective in Treating Anxiety Symptoms of Depression Dose-Finding Study: HAMD-17 Anxiety/Somatization Subscale The HAMD-17 Anxiety/Somatization subscale is an instrument consisting of items 10, 11, 12, 13, 15 and 17 on the HAMD-17 (anxiety- and somatization-related items). Duloxetine 80 mg/d produced significant improvement compared to placebo by Week 2 and the difference remained significant for the duration of the study. At Week 8, the difference between duloxetine 80 mg/d and paroxetine was statistically significant. Again, note that this study was not powered for comparisons among the active treatment groups; while this finding is interesting, it bears replication. ** P<.05 ** ** **p<0.01 vs placebo. Data on file, Lilly Research Laboratories.

60 Duloxetina vs Paroxetina: HAMA TotalKey Points: The Hamilton Anxiety Rating Scale (HAMA) is a validated measure of anxiety symptomatology and was used as a secondary efficacy measure in this study because of the frequency of comorbid anxiety symptoms in major depression. Duloxetine 80 mg/day had a significant anxiolytic effect in this study starting at week-2 and continuing at each timepoint throughout the study by mixed model repeated measures (MMRM) analysis. Background: This study data presented here are from one of two identical studies that examined the efficacy of lower (40 mg/day) and higher (80 mg/day) duloxetine doses given in a twice-daily dosing regimen as 20 mg BID or 40 mg BID. It also incorporated a paroxetine (20 mg/day) arm to compare duloxetine’s efficacy and tolerability with that of an SSRI, which acts only on the serotonin neurotransmitter. This was an 8-week, randomized, double-blind, controlled trial in outpatients who met DSM-IV criteria for major depression. None of the patients were considered treatment-refractory. Entry criteria included a DSM-IV diagnosis of major depression with a severity specified by a 17-item Hamilton Depression Rating Scale (HAMD-17) total score > 15 and a Clinical Global Impression of Severity (CGI-S) score of > 4 (indicating at least moderately ill) at baseline for out-patients at least 18 years of age. References: Goldstein D, Lu Y, Detke M, et al. “Duloxetine vs. Paroxetine in the Treatment of Depression”. Presented at the 155th Annual Meeting of the American Psychiatric Association (APA); Philadelphia, PA; May 18-23, 2002. Data: Weeks DLX 40 mg/day (n=84) DLX 80 mg/day (n=86) PRX 20 mg/day (n=84) Placebo (n=88) Study: F1J-MC-HMAT (B) Goldstein DJ, et al. Presented at the 155th Annual Meeting of the APA; Philadelphia, PA; May 18-23, 2002.

61 Análisis combinado de remisión en seis estudios controlados por placebo e ISRSTasas de Remisión en semana 8 (HAMD (HAMD < < 7) 7) 17 17 60 60 Duloxetine Duloxetina 50 50 40 40 - - 120 mg/día 120 mg/d * * *+ *+ ISRS 40 40 43% 43% * * 38% 38% 38% 38% Porcentaje de pacientes Placebo Placebo * * 30 30 28% 28% 29% 29% 20 20 *p<.05 *p<.05 vs. placebo vs. placebo 18% 18% Key Points: In this pooled analysis of all randomized patients in 6 placebo-controlled, SSRI comparator studies, the remission rates were 43% for duloxetine and 38% for SSRI, and 28% for placebo. In a subset of patients with a higher baseline HAMD17 scores (HAMD17 > 19) more commonly used in antidepressant trials, remission rates for duloxetine were statistically significantly greater than both SSRI and placebo. Remission was defined as a HAMD17 total score of < 7 at 8-weeks. Background: The data presented here are from six randomized, parallel-group, double-blind, placebo-controlled, SSRI-comparator studies in adult outpatients who met DSM-IV criteria for major depressive disorder (MDD). None of the patients were considered treatment-refractory. Entry criteria included a DSM-IV diagnosis of major depression with a severity specified by a 17-item Hamilton Depression Rating Scale (HAMD-17) total score > 15 and a Clinical Global Impression of Severity (CGI-S) score of > 4 (indicating at least moderately ill) at baseline for out-patients at least 18 years of age.The relatively low cut-off of 15 on the 17-item HAMD was chosen to minimize encouraging raters to artificially inflate baseline scores, to provide greater accuracy. Note that all patients still had to meet full DSM-IV criteria for MDD and have a CGI-S > 4. All of the studies used fixed dosing or forced titration dosing protocols. Duloxetine doses ranged from mg/day. SSRI doses were within the range of accepted effective dosing (fluoxetine 20 mg, paroxetine 20 mg), but were chosen for purposes other than head-to-head comparisons, such as non-inferiority analyses conducted to satisfy regulatory requirements. Because of this, results must be interpreted in light of the doses used. References: Thase ME, Lu Y, Joliat MJ, and Detke MJ. “Remission in Placebo-Controlled Trials of Duloxetine with an SSRI Comparator.” Presented at the 156th Annual Meeting of the APA; San Francisco, CA; May 17-22, 2003. Study: F1J-MC-HMAQ, F1J-MC-HMAT, F1J-MC-HMAY 10 10 +p=.013 +p=.013 vs. SSRI vs. SSRI LOCF Todos los randomizados (N) Pacientes con HAMD > > 19 (N) 19 (N) 17 17 Duloxetin Duloxetina ISRS Placebo Placebo Duloxetin Duloxetina ISRS Placebo Placebo 711 711 429 429 516 516 429 429 245 245 289 289 Thase ME, et al. Presented at the 156th Annual Meeting of the APA; San Francisco, CA; May 17-22, 2003.

62 Cymbalta: Estudios a largo plazoKey Point: I am presenting some information on a new drug from Lilly – it is under FDA review currently and has received an approvable letter.

63 Estudio Abierto a Largo PlazoPer. I del estudio 3-8 dias Periodo II del Estudio hasta 1 año Periodo III estudio 2 semanas Fase del estudio sin medicación Fase de Selección Fase de Terapia Abierta Duloxetina 60 mg BID Todos los Pacientes Duloxetina 40 mg BID Todos los Pacientes Duloxetina 40 mg BID Open-Label Long-Term Study A long-term safety exposure study included 1279 patients with a DSM-IV diagnosis of major depression, treated with open-label duloxetine for up to 1 year. Flexible dosing of duloxetine 40 to 60 mg twice daily was used. There was a 2-week follow-up period off study drug. Duloxetina 20 mg BID

64 Cambio promedio desde nivel basalMejora en la Escala HAMD de 17 Puntos Total Estudio Abierto a Largo Plazo Semanas Tasa de Respuesta al final = 79% Tasa de Remisión al final = 69% N=1161 Cambio promedio desde nivel basal Improvment in HAMD-17 Total Score Open-Label Long-Term Study The HAMD-17 score was significantly improved by duloxetine. Duloxetine maintained efficacy over chronic treatment in this study. The response rate at endpoint was 79% and the remission rate, 69%. Statistics The data points in this line graph (unlike all the others presented) are based upon observed cases; that is, patients who dropped out were not included in the calculation of means. Because the patients who respond better are more likely to remain in the trial, this technique is generally thought to artificially inflate results somewhat. Response and remission rates: Endpoint was defined as the last visit for each patient in the trial, regardless of when they discontinued. Patients stayed in the trial for a mean of approximately 8 months, but were evaluated for response/remission at endpoint, regardless of when it occurred. This was an intent-to-treat analysis, not a completer analysis, which is generally thought to underestimate effects. Data on file, Lilly Research Laboratories. Study F1J-MC-HMAU. Not approved for use in enduring materials

65 Duloxetina en estudio abierto a un año en el tratamiento del DDM: Probabilidad de RespuestaSemanas 10 10 20 20 30 30 40 40 50 50 Mejoría 100 100 Duloxetina Duloxetin 90 90 80 o 120 80 80 mg/día 70 70 (n=1279) (n=1279) 60 60 Probabilidad de Respuesta (%) 50 50 40 40 Key Points: Long-term efficacy data over 52-weeks in an open label study of 1279 patients with major depression showed a probability of response of > 70% at 6-weeks and > 90% at 52-weeks by mixed models repeated measures (MMRM) analysis. Patients were treated with duloxetine 80 or 120 mg/day. A total of 520 patients completed 52-weeks of treatment with duloxetine. Background: This was an open label study of duloxetine at doses up to 120 mg/day (given as a twice-daily divided dose) for the evaluation of long-term (52-weeks) safety in patients with major depression. Entry criteria included a DSM-IV diagnosis of major depression with a severity specified by a Clinical Global Impression of Severity (CGI-S) score of > 3 (indicating at least mildly ill) at baseline for out-patients at least 18 years of age. Patients were stabilized at duloxetine doses of 80 mg/day (46.7%) or 120 mg/day (49.3%), given as a twice-daily divided dose. Approximately 4% of patients had doses other than 80 or 120 mg/day, with the most common dose being 40 mg/day (3.4%). References: Raskin J, Goldstein DJ, Mallinckrodt CH, and Ferguson MB. Duloxetine in the Long-Term Treatment of Major Depressive Disorder. J Clin Psychiatry 2003;64: Data: weeks Duloxetine 80 or 120 mg per day (n = 1279) Study: F1J-MC-HMAU 30 30 20 20 10 10 MMRM MMRM Respuesta definida como un > 50% decremento en HAMD total desde basal. 17 Raskin J, et al. J Clin Psychiatry 2003;64:

66 Duloxetina en estudio abierto a un año en el tratamiento del DDM: HAMD17 Puntaje totalSemanas 10 10 20 20 30 30 40 40 50 50 MMRM Duloxetina Duloxetin 80 o 120 - - 4 4 mg/día (n=1279) (n=1279) - - 8 8 Total ) Mejoría Total Media de cambio 17 17 - - 12 12 Key Points: Duloxetine maintained efficacy over chronic treatment (52-weeks) in this study by mixed model repeated measures (MMRM) analysis. The HAMD17 total score at baseline was approximately 23 and decreased to 9, 6, and 5 at 6, 28, and 52 weeks respectively. Background: This was an open label study of duloxetine at doses up to 120 mg/day (given as a twice-daily divided dose) for the evaluation of long-term (52-weeks) safety in patients with major depression. Entry criteria included a DSM-IV diagnosis of major depression with a severity specified by a Clinical Global Impression of Severity (CGI-S) score of > 3 (indicating at least mildly ill) at baseline for out-patients at least 18 years of age. Patients were stabilized at duloxetine doses of 80 mg/day (46.7%) or 120 mg/day (49.3%), given as a twice-daily divided dose. Approximately 4% of patients had doses other than 80 or 120 mg/day, with the most common dose being 40 mg/day (3.4%). References: Raskin J, Goldstein DJ, Mallinckrodt CH, and Ferguson MB. Duloxetine in the Long-Term Treatment of Major Depressive Disorder. J Clin Psychiatry 2003;64: Data: Weeks Duloxetine 80 or 120 mg per day (n = 1279) Study: F1J-MC-HMAU (HAMD (HAMD - - 16 16 MMRM - - 20 20 Raskin J, et al. J Clin Psychiatry 2003;64:

67 Duloxetina a un año en el tratamiento del TDM: Probabilidad de RemisiónSemanas 10 10 20 20 30 30 40 40 50 50 Mejoría 90 90 Duloxetina 80 80 80 o 120 70 70 mg/día (n=1279) (n=1279) 60 60 Probabilidad de Remisión (%) 50 50 40 40 30 30 Key Points: Long-term efficacy data over 52-weeks in an open label study of 1279 patients with major depression showed a probability of remission of > 50% at 6-weeks and > 80% at 52-weeks by mixed models repeated measures (MMRM) analysis. Patients were treated with duloxetine 80 or 120 mg/day. A total of 520 patients completed 52-weeks of treatment with duloxetine. Background: This was an open label study of duloxetine at doses up to 120 mg/day (given as a twice-daily divided dose) for the evaluation of long-term (52-weeks) safety in patients with major depression. Entry criteria included a DSM-IV diagnosis of major depression with a severity specified by a Clinical Global Impression of Severity (CGI-S) score of > 3 (indicating at least mildly ill) at baseline for out-patients at least 18 years of age. Patients were stabilized at duloxetine doses of 80 mg/day (46.7%) or 120 mg/day (49.3%), given as a twice-daily divided dose. Approximately 4% of patients had doses other than 80 or 120 mg/day, with the most common dose being 40 mg/day (3.4%). References: Raskin J, Goldstein DJ, Mallinckrodt CH, and Ferguson MB. Duloxetine in the Long-Term Treatment of Major Depressive Disorder. J Clin Psychiatry 2003;64: Data: Weeks Duloxetine 80 or 120 mg per day (n = 1279) Study: F1J-MC-HMAU 20 20 10 10 MMRM MMRM Remisión definida como HAMD Punt.total de < 7. 17 Raskin J, et al. J Clin Psychiatry 2003;64:

68 Duloxetina en Largo plazo:1 año de estudio abierto para el tratamiento de DDM: Probabilidad de respuesta o remisión Semanas 6 6 28 28 52 52 Mejoría 100 100 90 90 91% Probabilidad de 88% 80 80 e Respuesta 81% 70 70 76% 71% Probabilidad de respuesta o 60 60 Remisión (%) 50 50 51% Probabilidad de 40 40 Remisión 30 30 Key Points: Long-term efficacy data over 52-weeks in an open label study of 1279 patients with major depression showed high, response and remission rates by mixed models repeated measures (MMRM) analysis. Patients were treated with duloxetine 80 or 120 mg/day. A total of 520 patients completed 52-weeks of treatment with duloxetine. Background: This was an open label study of duloxetine at doses up to 120 mg/day (given as a twice-daily divided dose) for the evaluation of long-term (52-weeks) safety in patients with major depression. Entry criteria included a DSM-IV diagnosis of major depression with a severity specified by a Clinical Global Impression of Severity (CGI-S) score of > 3 (indicating at least mildly ill) at baseline for out-patients at least 18 years of age. Patients were stabilized at duloxetine doses of 80 mg/day (46.7%) or 120 mg/day (49.3%), given as a twice-daily divided dose. Approximately 4% of patients had doses other than 80 or 120 mg/day, with the most common dose being 40 mg/day (3.4%). References: Raskin J, Goldstein DJ, Mallinckrodt CH, and Ferguson MB. Duloxetine in the Long-Term Treatment of Major Depressive Disorder. J Clin Psychiatry 2003;64: Data: weeks Probability of Response Probability of Remission Study: F1J-MC-HMAU 20 20 10 10 MMRM MMRM Duloxetina 80 o Duloxetine 80 o 120 mg/día (n=1279) Respuesta definida como > 50% decremental en HAMD total desde basal. 17 Remisión definida como HAMD total de < 7. 17 Raskin J, et al. J Clin Psychiatry 2003;64:

69 Duloxetina :Estudio a 1 año, abierto en DDM: Tasas de Respuesta y remisión al final10 20 30 40 50 60 70 80 90 100 Percentage of Patients 71% 60% LOCF Respuesta Remisión Duloxetina 80 o 120 mg/día (n=1279) Respuesta definida como un > 50% decremental en HAMD17 total desde basal. Remisión definida como un HAMD17 total de < 7. Key Point: LOCF analysis also revealed high response and remission rates. Both MMRM and LOCF analyses showed that those patients who responded were likely to also remit. Background: This was an open label study of duloxetine at doses up to 120 mg/day (given as a twice-daily divided dose) for the evaluation of long-term (52-weeks) safety in patients with major depression. Entry criteria included a DSM-IV diagnosis of major depression with a severity specified by a Clinical Global Impression of Severity (CGI-S) score of > 3 (indicating at least mildly ill) at baseline for out-patients at least 18 years of age. Patients were stabilized at duloxetine doses of 80 mg/day (46.7%) or 120 mg/day (49.3%), given as a twice-daily divided dose. Approximately 4% of patients had doses other than 80 or 120 mg/day, with the most common dose being 40 mg/day (3.4%). References: Raskin J, Goldstein DJ, Mallinckrodt CH, and Ferguson MB. Duloxetine in the Long-Term Treatment of Major Depressive Disorder. J Clin Psychiatry 2003;64: Data: % Response 71 Remission 60 Study: F1J-MC-HMAU Raskin J, et al. J Clin Psychiatry 2003;64:

70 Cymbalta vs VenlafaxinaKey Point: I am presenting some information on a new drug from Lilly – it is under FDA review currently and has received an approvable letter.

71 Estudio HMDW Sistema Límbico Corteza Prefrontal Locus Coeruleus(fuente NA) Serotonin and Norepinephrine in Depression Most of the serotonin in the central nervous system is produced in the raphe nuclei. The largest cluster of noradrenergic cells in the central nervous system is located in the locus ceruleus. Both of these sources have ascending tracts which project to brain regions thought to be involved in depressive symptoms. Both also have descending tracts. Núcleo del Rafe (fuente 5-HT )

72 Cymbalta vs EscitalopramKey Point: I am presenting some information on a new drug from Lilly – it is under FDA review currently and has received an approvable letter.

73 Diseño del estudio: Fase AgudaKey Points: This was an 8-week, randomized, double-blind, fixed-dose, active comparator and placebo-contolled study used to assess the onset of antidepressant action of duloxetine (60 mg QD) vs. escitalopram (10 mg QD) and placebo in patients with major depressive disorder (MDD). Patients were randomized 2:2:1 for duloxetine, escitalopram, and placebo respectively. This study incorporated a double-blind, variable-length, placebo lead-in period. Investigators and patients were blinded to the start of active treatment, the timepoint of primary objective measurement, and the endpoint of the acute treatment phase. The study employed parallel dosing schedules. Duloxetine treatment was initiated and maintained at 60 mg QD, and escitalopram treatment was initiated and maintained at 10 mg/day during the 8-week acute treatment. This study included a 6-month blinded extension phase in which flexible dose optimization and a placebo rescue was available. Investigators and patients were blinded to the timing of dose increases as well as the criteria for allowing dose increases or placebo rescue. Results from the extension phase will be available at a later date. In an effort to reduce the impact of artificial inflation of baseline MDD severity scores, the Montgomery-Asberg Depression Rating Scale (MADRS) was used to screen patients for the study, and the 17-item Hamilton Depression Rating Scale (HAMD-17) was defined as the primary efficacy measure. Background: The patient population was adult outpatients who met DSM-IV criteria for major depressive disorder (MDD). Patients were not considered treatment-refractory. Entry criteria included a DSM-IV diagnosis of major depression with a severity specified by a Montgomery-Asberg Depression Rating Scale (MADRS) total score > 22 and a Clinical Global Impression of Severity (CGI-S) score of > 4 (indicating at least moderately ill) at baseline for out-patients at least 18 years of age. All patients were required to take 6 capsules of study drug daily for their entire participation (8 months). Study: F1J-US-HMCR Nierenberg AA. et al. Onset of Antidepressant Action and Acute Efficacy and Safety of Duloxetine Versus Escitalopram and Placebo in the Treatment of Major Depressive Disorder. Presented at the Annual American College of Neuropharmacology (ACNP) Meeting. Waikoloa, HI. December 11-15, 2005.

74 Objetivo Primario: Inicio de Acción Antidepresiva: Disminución 20% en la subescala Maier en semana 2 y efecto sostenido a través de 8 semanas de tratamiento agudo Key Points: Duloxetine was non-inferior to escitalopram in onset of antidepressant action. Both drugs separated significantly from placebo at week-2. Probabilities of meeting onset criteria for duloxetine-, escitalopram-, and placebo-treated patients were 42.6%, 35.2%, and 21.5% respectively. Onset of action was defined as a 20% decrease from baseline in the 17-item Hamilton Rating Scale for Depression (HAMD17) Maier subscale that was maintained or exceeded at all subsequent visits. The Maier subscale includes HAMD-17 items that represent the core emotional symptoms of depression (item-1, depressed mood; item-2, feelings of guilt; item-7, work and activities; item-8, retardation; item-9, agitation; and item-10, psychic anxiety). Background: This was an 8-week, randomized, double-blind, fixed-dose, active comparator and placebo-contolled study used to assess the onset of antidepressant action of duloxetine vs. escitalopram and placebo in patients with major depressive disorder (MDD). Patients were randomized 2:2:1 for duloxetine, escitalopram, and placebo respectively. This study incorporated a double-blind, variable-length, placebo lead-in period. Investigators and patients were blinded to the start of active treatment, the timepoint of primary objective measurement, and the endpoint of the acute treatment phase. In an effort to reduce the impact of artificial inflation of baseline MDD severity scores, the Montgomery-Asberg Depression Rating Scale (MADRS) was used to screen patients for the study, and the 17-item Hamilton Depression Rating Scale (HAMD-17) was defined as the primary efficacy measure. The patient population was adult outpatients who met DSM-IV criteria for major depressive disorder (MDD). Patients were not considered treatment-refractory. Entry criteria included a DSM-IV diagnosis of major depression with a severity specified by a Montgomery-Asberg Depression Rating Scale (MADRS) total score > 22 and a Clinical Global Impression of Severity (CGI-S) score of > 4 (indicating at least moderately ill) at baseline for out-patients at least 18 years of age. All patients were required to take 6 capsules of study drug daily for their entire participation (8 months). Study: F1J-US-HMCR Nierenberg AA. et al. Onset of Antidepressant Action and Acute Efficacy and Safety of Duloxetine Versus Escitalopram and Placebo in the Treatment of Major Depressive Disorder. Presented at the Annual American College of Neuropharmacology (ACNP) Meeting. Waikoloa, HI. December 11-15, 2005.

75 HAMD-17 Maier puntaje de la subescala: Curso de tratamiento a lo largo del tiempoKey Points: In mean change on the primary efficacy measure (HAMD 17 Maier subscale score), the duloxetine treatment group improved significantly vs. placebo at all timepoints during the acute treatment phase (p < .05). Escitalopram showed significant separation from placebo at all timepoints except week-3. By main effect of treatment, the difference in treatment effect on the HAMD-17 Maier subscale score was statistically significant for duloxetine vs. escitalopram. The Maier subscale includes HAMD17 items that represent the core emotional symptoms of depression (item-1, depressed mood; item-2, feelings of guilt; item-7, work and activities; item-8, retardation; item-9, agitation; and item-10, psychic anxiety). The main effect of treatment analysis estimates the treatment effects pooled across all patient visits and is similar to an area under the curve analysis. Background: This was an 8-week, randomized, double-blind, fixed-dose, active comparator and placebo-contolled study used to assess the onset of antidepressant action of duloxetine vs. escitalopram and placebo in patients with major depressive disorder (MDD). Patients were randomized 2:2:1 for duloxetine, escitalopram, and placebo respectively. This study incorporated a double-blind, variable-length, placebo lead-in period. Investigators and patients were blinded to the start of active treatment, the timepoint of primary objective measurement, and the endpoint of the acute treatment phase. In an effort to reduce the impact of artificial inflation of baseline MDD severity scores, the Montgomery-Asberg Depression Rating Scale (MADRS) was used to screen patients for the study, and the 17-item Hamilton Depression Rating Scale (HAMD-17) was defined as the primary efficacy measure. The patient population was adult outpatients who met DSM-IV criteria for major depressive disorder (MDD). Patients were not considered treatment-refractory. Entry criteria included a DSM-IV diagnosis of major depression with a severity specified by a Montgomery-Asberg Depression Rating Scale (MADRS) total score > 22 and a Clinical Global Impression of Severity (CGI-S) score of > 4 (indicating at least moderately ill) at baseline for out-patients at least 18 years of age. All patients were required to take 6 capsules of study drug daily for their entire participation (8 months). Study: F1J-US-HMCR Nierenberg AA. et al. Onset of Antidepressant Action and Acute Efficacy and Safety of Duloxetine Versus Escitalopram and Placebo in the Treatment of Major Depressive Disorder. Presented at the Annual American College of Neuropharmacology (ACNP) Meeting. Waikoloa, HI. December 11-15, 2005.

76 Perfil de Remisión: Tratamiento agudo a lolargo del tiempoKey Points: There were no significant between-group differences in the probabilities of remission (HAMD17 total score < 7) at Week 8 - duloxetine 40.1%, escitalopram 33.0%, placebo 27.7%. Duloxetine showed a statistically significant separation from placebo at week 6. Background: This was an 8-week, randomized, double-blind, fixed-dose, active comparator and placebo-contolled study used to assess the onset of antidepressant action of duloxetine vs. escitalopram and placebo in patients with major depressive disorder (MDD). Patients were randomized 2:2:1 for duloxetine, escitalopram, and placebo respectively. This study incorporated a double-blind, variable-length, placebo lead-in period. Investigators and patients were blinded to the start of active treatment, the timepoint of primary objective measurement, and the endpoint of the acute treatment phase. In an effort to reduce the impact of artificial inflation of baseline MDD severity scores, the Montgomery-Asberg Depression Rating Scale (MADRS) was used to screen patients for the study, and the 17-item Hamilton Depression Rating Scale (HAMD-17) was defined as the primary efficacy measure. The patient population was adult outpatients who met DSM-IV criteria for major depressive disorder (MDD). Patients were not considered treatment-refractory. Entry criteria included a DSM-IV diagnosis of major depression with a severity specified by a Montgomery-Asberg Depression Rating Scale (MADRS) total score > 22 and a Clinical Global Impression of Severity (CGI-S) score of > 4 (indicating at least moderately ill) at baseline for out-patients at least 18 years of age. All patients were required to take 6 capsules of study drug daily for their entire participation (8 months). Study: F1J-US-HMCR Remission was defined as a HAMD-17 total score of < 7. Probabilities of remission at 8-weeks for placebo, duloxetine and escitalopram were 27.7%, 40.1%, and 33.0%, respectively Nierenberg AA. et al. Onset of Antidepressant Action and Acute Efficacy and Safety of Duloxetine Versus Escitalopram and Placebo in the Treatment of Major Depressive Disorder. Presented at the Annual American College of Neuropharmacology (ACNP) Meeting. Waikoloa, HI. December 11-15, 2005.